Myeloid cells are an important group of immune cells that represent the first line of defense against different pathogens and can be divided into granulocytic and monocytic subpopulations. Granulocytic myeloid cells (polymorphonuclear granulocytes or neutrophils, eosinophil granulocytes, and basophil granulocytes) are the first line of immune defense during bacterial, viral or parasitic infections. Among them, polymorphonuclear cells (PMN) play an essential role in the defense against extracellular bacteria, while eosinophils regulate immune defense against parasites. In addition, eosinophil granulocytes and basophil granulocytes are involved in the development of allergic reactions. Monocytic myeloid cells (dendritic cells, macrophages) play an essential role in phagocytosis and in the processing and presentation of antigens.
Under pathological conditions, the differentiation homeostasis of myeloid cells is impaired, leading to the accumulation of Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells characterized by their suppressive actions on innate and adaptive immune cells such as T cells, dendritic cells, and natural killer (NK) cells. MDSC inhibit T- and NK cell responses through several pathways including the increased expression of arginase I, inducible nitric oxide synthase (iNOS), and gp91phox, and the high release of reactive oxygen species (ROS), peroxynitrites (PNT), and prostaglandin E2 (PGE2).
In addition to their immunoregulatory activity, MDSC also promote tumor angiogenesis and metastasis. MDSCs can be divided into granulocytic and monocytic subsets based on different markers and morphological features. Both types of cells are also produced during tissue damage caused either by trauma (surgical or other), chronic infectious diseases, and by the growth of tumors. In the first case, both granulocytic and monocytic cells play an essential role in the healing of the damaged tissues. In other forms of chronic disease such as cancer, autoimmunity or chronic infection, these cells are also produced initially with the goal of “healing” damaged tissues, however the chronic nature of these diseases and the inability of the myeloid cells to heal the damage turns these cells into chronic inflammatory cells which in turn suppress the T- and B cell immune response.
Multiple pro-inflammatory mediators present in the tumor microenvironment induce the generation and accumulation of MDSCs. The numbers of MDSCs increase with cancer burden, a problematic event since MDSCs are also shown to inhibit immune cancer therapeutics and immunotherapy. The inhibitory role of MDSC is widely accepted as a major obstacle for immunotherapy. They not only represent a major obstacle in the successful development of different forms of immunotherapy, but are also an attractive therapeutic target. Minimizing MDSC-mediated immunosuppression is important not only to developing novel therapeutics, but also in increasing the effectiveness of therapeutics currently used.
MDSC produce several factors that can block the immune function, factors which normally function to minimize unwanted tissue damage. Unfortunately, this often prevents a protective immune response mediated by T cells, NK calls and B cells, for example. Among these factors that inhibit the immune function are Arginase (I and II) that consume arginine in the microenvironment, nitric oxide synthase (NOS) which consumes arginine and makes nitric oxide, nitric oxide (NO) which is able to induce apoptosis of T cells and inhibit the function of cellular receptors in T cells, and hydrogen peroxide (H2O2) that also induces T cell apoptosis. In cancer, for example, great efforts have been made to block one or more of these different immunosuppressive mediators with the goal of preventing unwanted immunosuppression and allowing the immune system to eliminate the malignant cells. Unfortunately, the multiple redundant pathways that MDSC use to block the immune response and the ability of the bone marrow to produce up to 10e11 MDSC daily have prevented these approaches from having any significant effect.